Hepatitis A virus (HAV), a picornavirus, is the causative agent of acute hepatitis. Like other picornaviruses, HAV is assumed to enter the cell by first binding to a specific cellular receptor. Interaction of HAV with its cellular receptor could be responsible for many characteristics of HAV such as growth restriction in primate cells and hepatovirulence. Therefore, study of the interaction of HAV with its cellular receptor will help to understand the mechanisms involved in the pathogenicity of this virus and specific receptor antagonists could be useful therapeutic agents. Furthermore, identification of the HAV cellular receptor may lead to the development of small animal models for HAV infection. Such a model would be important for the testing of potency of future HAV vaccines. A monoclonal antibody to the surface of primary AGMK cells has been provided by Moritsugu of Japan NIH, has been shown to be directed against a surface antigen of primary AGMK cells. This McAb blocks the infection of those cells with HAV through a series of steps, the cDNA for this receptor has been cloned. Several nonprimate cells lines that could not be infected directly with HAV have now been infected after they were first transfected with the cDNA clone of the putative receptor. Sequence analysis of the CDNA reveals that it codes for a glycoprotein that has not previously been described but that seems to be related to known mucin proteins. Northern and Southern blotting has shown that humans have a related gene that is expressed in a variety of organs including liver. It has not been determined yet if this related protein also functions as a receptor for HAV. At present this cDNA is being inserted into baculovirus expression systems so that it can be over expressed and better characterized. We are planning to develop transgenic mice that express this HAV receptor with the hope to create a small animal model for HAV that would be useful for vaccine development and evaluation as well as pathogenesis studies. This is the first cellular receptor for any of the the 5 hepatitis viruses that has been identified.